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Мурзабекова, М. А., Я. М. Марченко, Д. И. Шихбабаева, and О. Ю. Виноградова. "Genetic Aspects Classical Ph-negative Myeloproliferative Neoplasms (Literature Review)." Гематология. Трансфузиология. Восточная Европа 10, no. 2 (2024): 210–18. http://dx.doi.org/10.34883/pi.2024.10.2.001.
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Рh-негативные миелопролиферативные новообразования – это группа заболеваний, которые характеризуются клональной пролиферацией одной или нескольких клеточных линий миелоидных предшественников, а также соединительнотканных компонентов костного мозга и сопровождаются изменениями показателей крови. В соответствии с классификацией Всемирной организации здравоохранения 2022 года к Ph-негативным новообразованиям относятся истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз, хронический нейтрофильный лейкоз, хронический эозинофильный лейкоз, ювенильный миеломоноцитарный лейкоз и миелопролиферативное новообразование, неклассифицируемое. Патогенез миелопролиферативных новообразований связан с клональной пролиферацией неопластически измененной стволовой клетки. При этом центральным патогенетическим механизмом является независимая от цитокинов активация пути JAK-STAT, приводящая к изменениям экспрессии генов, которые вызывают патологическую пролиферацию и дальнейшее функциональное нарушение костного мозга. К активации JAK/ STAT-сигнального пути приводят так называемые драйверные мутации: замена фенилаланина на валин в 617-м положении гена янускиназы второго типа (JAK2V617F), мутации в 9-м экзоне гена кальретикулина (CALR), в гене рецептора тромбопоэтина (MPL), а также эпигенетические мутации, такие как SF3B1, ТР53, ASXL1, ETV6, RUNX1, GATA2, DNMT3A, TET2, IDH1/2, SRSF2, SETBP1, NRAS/KRAS, CBL, PTPN11, EZH2. В статье представлен обзор литературы, посвященный генетическим аспектам миелопролиферативных новообразований, представляющих важность как для диагностики, так и для оценки риска прогрессирования заболеваний. Ph-negative myeloproliferative neoplasms are a group of diseases characterized by clonal proliferation of one or more cell lines of myeloid precursors, as well as connective tissue components of the bone marrow and accompanied by changes in blood parameters. According to the classification of the World Health Organization 2022, classic Ph-negative neoplasms include polycythemia vera, essential thrombocytemia and primary myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia and myeloproliferative neoplasm, unclassified. The pathogenesis of myeloproliferative neoplasms is associated with clonal proliferation of neoplastically formed stem cells. The central pathogenetic mechanism is cytokine- independent activation of the JAK-STAT pathway, leading to changes in gene expression that cause pathological proliferation and further functional impairment of the bone marrow. The activation of the JAK/STAT signaling pathway is caused by so-called driver mutations: replacement of phenylalanine with valine at position 617 of the type II januskinase gene (JAK2V617F), mutations in exon 9 of the calreticulin gene (CALR), in the thrombopoietin receptor gene (MPL), as well as epigenetic mutations such as SF3B1, TP53, ASXL1, ETV6, RUNX1, GATA2, DNMT3A, TET2, IDH1/2, SRSF2, SETBP1, NRAS/KRAS, CBL, PTPN11, EZH2. The article presents a review of the literature on the genetic aspects of myeloproliferative neoplasms, which are important both for the diagnosis and for assessment of the risk of complications and disease progression.
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Martinkov, V. N., D. K. Novik, I. V. Veyalkin, A. E. Silin, and I. A. Iskrov. "The incidence of Ph-negative chronic myeloproliferative neoplasms in Belarus." Russian journal of hematology and transfusiology 68, no. 3 (2023): 363–72. http://dx.doi.org/10.35754/0234-5730-2023-68-3-363-372.
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Introduction. Ph-negative myeloproliferative neoplasms (MPN) are chronic clonal disorders characterized by the proliferation of mature cells from one or more myeloid cell lines. These disorders include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The incidence of classical Ph-negative MPN varies significantly throughout the world. These differences may be due to geographical or population features, as well as due to differences in methods of diagnosis and recording. Aim: to determine incidence of Ph-negative MPN in Belarus. Materials and methods. Data on all cases of newly diagnosed Ph-negative MPNs (PV, ET and PMF) for 2014-2018 were collected from central regional medical institutions with a hematology specialization. Population epidemiological analysis of incidence was carried out by determining crude incidence rates per 100 000 population per year with distribution by genderand age groups at diagnosis, age-standardized rates, as well as average annual percent change. Results. The overall annual standardized incidence rate of classical Ph-negative MPN in Belarus was 1.96 (1.86–2.07), PV — 0.93 (0.86–1.01), ET — 0.63 (0.57–0.70) and PMF — 0.40 (0.36–0.45) per 100 000 population per year, respectively. The overall crude incidence rate was 3.26 (3.10–3.43) per 100 000 population. The crude incidence rates increased steadily with the increase in age of patients with a peak value of 12.78 (10.97–14.81) in the age group of 70–74 years. No significant changes were revealed in the overall incidence of the MPN and for each of the studied diseases separately during the study period. Conclusion. For the first time the nationwide features of incidence of the Ph-negative MPN in Belarus were estimated, which made it possible to provide substantial information for public health management. The incidence of MPN in Belarus is generally comparable to the levels determined in the analysis of the populations of other countries.
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Polyakov, A. S., V. V. Tyrenko, Ya A. Noskov, D. K. Zhogolev, and A. V. Kovalev. "Clinical and laboratory features of different types of interferon therapy classic Ph-negative myeloproliferative neoplasms." Genes & Cells 11, no. 3 (2016): 153–61. http://dx.doi.org/10.23868/gc120618.
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Chronic myeloproliferative neoplasms are a group of disorders characterized by clonal disturbance of pluripotent bone marrow stem cells, leading to an excessive increase in hematopoietic cells that retain the ability to differentiate. Modern screening techniques have made changes to the current view of the epidemiology of myeloproliferative neoplasms. Recently, more and more researches are found with the median age below 50 years, and sometimes less than 40 years. This circumstance determines the need to improve therapy with the use of interferon-а. A new stage in the treatment of myeloproliferative neoplasms is the use of pegylated forms of interferon. A feature of this drug is more uniform release of interferon from copolymer combinations that results in a more effective action of the basic substance, reduced maximum weekly dose of the drug, reduce the severity of side effects, better tolerability, as well as better control of the disease progression. At the moment, even the proportion of patients receiving conventional interferon-а is very small. Therapy with pegylated interferon insufficiently developed. There are only a number of retrospective studies in recent years, indicating the usefulness of pegylated interferon to control the disease and improve the prognosis. According to the work pegylated interferon therapy is the most modern and effective approach to the treatment of chronic myeloproliferative neoplasms. We have studied the possibility of using of various forms of interferon-а for the treatment of myeloproliferative neoplasms.
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Bittencourt, Rosane Isabel, Jose Vassallo, Maria de Lourdes Lopes Ferrari Chauffaille, et al. "Philadelphia-negative chronic myeloproliferative neoplasms." Revista Brasileira de Hematologia e Hemoterapia 34, no. 2 (2012): 140–49. http://dx.doi.org/10.5581/1516-8484.20120034.
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Tarakanova, A. V., D. S. Abramov, A. V. Pshonkin, and D. M. Konovalov. "Pathomorphological diagnosis of Ph-negative chronic myeloproliferative neoplasms in children." Pediatric Hematology/Oncology and Immunopathology 23, no. 3 (2024): 123–29. http://dx.doi.org/10.24287/1726-1708-2024-23-3-123-129.
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BCR::ABL/Ph-negative chronic myeloproliferative neoplasms (CMPN) in children differ from those in adults in clinical manifestations and genetic alterations. Taking into account the well-known physiology of hematopoiesis in children, it seems important to compare the histological features of CMPN in pediatric patients with the criteria for the diagnosis of these diseases in adults specified in the World Health Organization (WHO) classification. In pediatric practice, the interpretation of changes in hematopoiesis in patients with CMPN without any established driver mutation has a particular importance for differential diagnosis with secondary thrombocytosis and erythrocytosis. For our analysis, we used bone marrow trephine biopsy specimens from the biobank of the Pathology Department of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. They had been obtained between 2016 and 2023 from 70 patients for initial histological examination. The final clinical diagnosis for these patients was CMPN. The frequency of the most common histological changes in hematopoiesis was assessed retrospectively. We compared our results with the data from the WHO classification, analysed the differences in morphological changes in the subgroups of patients with essential thrombocythemia with an established mutation or without it, assessed the relationship between the morphological changes and clinical symptoms of CMPN. The changes in hematopoiesis in children with CMPN are predominantly similar to those in adults, however there are differences in the morphology of megakaryocytes (scarcity of giant cells with hypersegmented nuclei (staghorn-like), an increased number of small and naked nuclei cells). In addition, bone marrow cellularity assessment has a low diagnostic value in differentiating between essential thrombocythemia and polycythemia vera in children. There are no differences in morphology in the subgroups of patients with essential thrombocythemia with an established mutation or without it. No statistically significant association between clinical symptoms of the disease and any of the morphological features of CMPN was found. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation.
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Ryabukhina, Yu E., P. A. Zeynalova, O. I. Timofeeva, et al. "Combination approach to diagnosis and treatment of an elderly patient with chronic Ph-negative myeloproliferative neoplasm and concomitant surgical pathology. Clinical observation." MD-Onco 1, no. 1 (2021): 61–65. http://dx.doi.org/10.17650/2782-3202-2021-1-1-61-65.
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Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.
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Hasserjian, Robert P. "The spectrum of Ph-negative disease: CNL and CSF3R-related disorders." Hematology 2024, no. 1 (2024): 270–78. https://doi.org/10.1182/hematology.2024000555.
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Abstract Chronic neutrophilic leukemia (CNL) is a very rare myeloid neoplasm characterized by peripheral blood neutrophilia and a hypercellular marrow with increased granulopoiesis. An activating mutation in CSF3R is present in 80% to 90% of cases. CNL displays some biological overlap in terms of clinical presentation and behavior, as well as genetic profile, with several other myeloid neoplasms, particularly myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and other MPN. Distinguishing these related entities can be challenging, requires close attention to peripheral blood and bone marrow morphology, and can be informed by the mutation pattern: CNL is strongly associated with CSF3R mutation, usually lacks JAK2, MPL, or CALR mutations, and, by definition, lacks BCR::ABL1 rearrangement. Pitfalls in diagnosis include subjectivity in assessing neutrophil dysplasia and distinguishing true neoplastic neutrophilia from reactive neutrophilias that may be superimposed upon or occur as a manifestation of the progression of other myeloid neoplasms. Accurate distinction between neutrophilic myeloid neoplasms is important, as it helps guide patient management and may disclose specific genetic lesions amenable to targeted therapy.
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Nann, Dominik, and Falko Fend. "Synoptic Diagnostics of Myeloproliferative Neoplasms: Morphology and Molecular Genetics." Cancers 13, no. 14 (2021): 3528. http://dx.doi.org/10.3390/cancers13143528.
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The diagnosis of a myeloid neoplasm relies on a combination of clinical, morphological, immunophenotypic and genetic features, and an integrated, multimodality approach is needed for precise classification. The basic diagnostics of myeloid neoplasms still rely on cell counts and morphology of peripheral blood and bone marrow aspirate, flow cytometry, cytogenetics and bone marrow trephine biopsy, but particularly in the setting of Ph− myeloproliferative neoplasms (MPN), the trephine biopsy has a crucial role. Nowadays, molecular studies are of great importance in confirming or refining a diagnosis and providing prognostic information. All myeloid neoplasms of chronic evolution included in this review, nowadays feature the presence or absence of specific genetic markers in their diagnostic criteria according to the current WHO classification, underlining the importance of molecular studies. Crucial differential diagnoses of Ph− MPN are the category of myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2, and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). This review focuses on morphological, immunophenotypical and molecular features of BCR-ABL1-negative MPN and their differential diagnoses. Furthermore, areas of difficulties and open questions in their classification are addressed, and the persistent role of morphology in the area of molecular medicine is discussed.
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Polushkina, Lyubov, Irina Martynkevich, Vasily Shuvaev, et al. "Genetic and Epigenetic Alterations of Ph-Negative Myeloproliferative Neoplasms." Blood 124, no. 21 (2014): 5549. http://dx.doi.org/10.1182/blood.v124.21.5549.5549.
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Abstract Objectives and background: Genetic mutations result in abnormalities of myelopoietic proteins and lie in the basis of Ph-negative myeloproliferative neoplasms (MPNs) development and its subsequent progression. Several somatic mutations in JAK2, MPL, TET2, EZH2, ASXL1, CBL, IDH1, IDH2, IKZF1 genes were detected in chronic and blastic phase MPNs. Recent studies have revealed a number of epigenetic alterations that contribute to Ph-negative MPNs pathogenesis and determine the clinical outcome. Mutations involving the EZH2 gene are thought to result in loss of methyltransferase activity suggesting a potential role of tumor suppressor gene silencing as a mechanism in the disease progression. Decrease in ubiquitin ligase activity caused by mutations CBL gene leads to myeloid proliferation. EZH2, CBL mutations are thought to be of prognostic value in MPN’s at the time of transformation to the blastic phase but data are inconsistent and require the further verification.The goal of our research was to determine the significance of mutations genes EZH2, CBL in the diagnosis and prognosis of Ph-negative MPNs. Methods. We have examined 102 patients with Ph-negative MPNs (45 pts with PV, 30 pts with ET and 27 pts with PMF). For all patients the detection of V617F mutation of JAK2 gene was done. V617F-negative pts with PV and pts with ET or PMF underwent the analysis of mutations in 12-th exon of JAK2 and 515 codone of MPL gene respectively. For 80 pts (30 with PV, 28 with ET and 22 with PMF) cytogenetic analysis and EZH2 mutation status were performed. Identification of CBL mutations was performed in 24 patients with available RNA samples. Mutations in 8, 10, 17, 18, 19 exons of EZH2 and RING-domen of CBL were defined by sequence analysis. V617FJAK2 mutation was detected in 44/45 (97,8%) pts with PV, 16/30 (53,3%) pts with ET and 13/27 (48,1%) pts with PMF. 538-539del-insL in 12-th exon of JAK2 was found in 1/45 (2,22%) patient with PV. W515KMPL mutation was identified in 1/30 (3,33%) pt with ET and 1/27 (3,7%) pt with PMF. 2 mutations of EZH2 gene have been found in 2 individuals with PMF (2/22). Both mutations are located in the 19 exon. The Ile713Thr mutation was detected in the patient with a del(6)(q15) karyotype which is associated with an intermediate cytogenetics risk. This patient subsequently underwent transformation from PMF to myelodysplastic syndrome in 9 months after the disease onset. Another case of mutation harboring (Thr731Asp) was detected in a patient with PMF and poor prognosis karyotype (chromosome 7 monosomy). This patient had transformation PMF to acute myeloid leukemia and died after 20 months. Homozygous mutation Q420R in CBL gene was detected in 1/24 patient with complex karyotype. Disease progression was observed after 16 months from the diagnosis. Conclusion. Mutations in EZH2 and CBL genes could be assessed as additional prognostic markers of unfavourable prognosis in patients with BCR-ABL-negative MPNs with different chromosomal aberrations. The integration of cytogenetic and molecular analyses could be a valuable option for stratification of patients and optimising the treatment strategy. References: Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010; 24:1128–1138. Disclosures No relevant conflicts of interest to declare.
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Paciaroni, Katia, Selenia Campagna, Nicoletta Villiva', et al. "CO-OCCURRENCE OF JAK2/CALR-POSITIVE MYELOPROLIFERATIVE DISORDER AND BCR-ABL-POSITIVE CHRONIC MYELOGENOUS LEUKAEMIA TREATED WITH COMBINATION OF TYROSINE KINASE INHIBITORS AND RUXOLITINIB." Mediterranean Journal of Hematology and Infectious Diseases 17, no. 1 (2025): e2025023. https://doi.org/10.4084/mjhid.2025.023.
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The concomitant presence of BCR-Abl1 and JAK2/CALR mutations in Myeloproliferative neoplasms (MPNs) is rare. The clinical presentation of Chronic Myelogenous Leukemia (CML) and Ph-negative MPN may vary, but CML seems to play a dominant role, so patients usually receive treatment with tyrosine kinase inhibitor (TKI) only. The second Ph-negative MPN becomes evident under the selective pressure of the TK.I.
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Lindholm Sørensen, Anders, and Hans Carl Hasselbalch. "Smoking and philadelphia-negative chronic myeloproliferative neoplasms." European Journal of Haematology 97, no. 1 (2015): 63–69. http://dx.doi.org/10.1111/ejh.12684.
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Cazzola, Mario, Luca Malcovati, and Rosangela Invernizzi. "Myelodysplastic/Myeloproliferative Neoplasms." Hematology 2011, no. 1 (2011): 264–72. http://dx.doi.org/10.1182/asheducation-2011.1.264.
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Abstract According to the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, myelodysplastic/myeloproliferative neoplasms are clonal myeloid neoplasms that have some clinical, laboratory, or morphologic findings that support a diagnosis of myelodysplastic syndrome, and other findings that are more consistent with myeloproliferative neoplasms. These disorders include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (BCR-ABL1 negative), juvenile myelomonocytic leukemia, and myelodysplastic/myeloproliferative neoplasms, unclassifiable. The best characterized of these latter unclassifiable conditions is the provisional entity defined as refractory anemia with ring sideroblasts associated with marked thrombocytosis. This article focuses on myelodysplastic/myeloproliferative neoplasms of adulthood, with particular emphasis on chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts associated with marked thrombocytosis. Recent studies have partly clarified the molecular basis of these disorders, laying the groundwork for the development of molecular diagnostic and prognostic tools. It is hoped that these advances will soon translate into improved therapeutic approaches.
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Novik, D., V. Martinkov, I. Veyalkin, et al. "Regional features of the incidence of chronic Ph-negative myeloproliferative neoplasms in Belarus." Medical and Biological Problems of Life Activity, no. 1 (May 22, 2023): 67–74. http://dx.doi.org/10.58708/2074-2088.2023-1(29)-67-74.
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According to published data, there are differences in the registered incidence of chronic Ph-negative myeloproliferative neoplasms (MPN) in some regions of the world. In this study, for the first time, we compare the Ph- MPN incidence in the regions of Belarus in order to determine the regional features.It was shown that for the period 2014-2018 the highest rates of standardized incidence of polycythemia vera were noted in the Brest region – 1,17 and Minsk – 1,11, the lowest incidence rate was determined in the Vitebsk region – 0,68 per 100,000 population per year, p<0,05. The maximum incidence rates of essential thrombocythemia were recorded in Minsk city – 1,04 and Gomel region – 0,86, which is significantly higher than in Minsk region – 0,27, Vitebsk region – 0,35 and Grodno region – 0,44 per 100 000 population per year. The highest incidence rates of primary myelofibrosis were noted in Gomel – 0,63 and Vitebsk regions – 0,53, they were significantly higher than in Grodno – 0,14 and Minsk regions – 0,24 per 100 000 population per year.Differences in the incidence of Ph-MPN between the regions of Belarus were revealed, while the overall incidence rates in Minsk city, Gomel, Brest and Mogilev regions exceeded those in Vitebsk, Grodno and Minsk regions. In addition, variation in incidence rates for individual nosologies was noted. The information obtained can be used to make management decisions when organizing medical observation and treatment of patients with Ph- MPN in Belarus.
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Santos, Fabio P. S., Renato D. Puga, Ricardo Helman, et al. "Whole Exome Sequencing of Philadelphia-Negative (Ph-negative) Myeloproliferative Neoplasms (MPNs) and Myelodysplastic/Myeloproliferative Disorders (MDS/MPD)." Blood 124, no. 21 (2014): 4593. http://dx.doi.org/10.1182/blood.v124.21.4593.4593.
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Abstract Introduction: The development of next-generation sequencing has made it feasible to interrogate the entire genome or exome (coding genome) in a single experiment. Accordingly, our knowledge of the somatic mutations that cause cancer has increased exponentially in the last years. MPNs and MDS/MPD are chronic myeloid neoplasms characterized by an increased proliferation of one or more hematopoietic cell lineages, and an increased risk of transformation to acute myeloid leukemia (AML). MPNs and MDS/MPDs are heterogenous disorders, both in clinical presentation and in prognosis. We sought to determine the genetic landscape of Ph-negative MPNs and MDS/MPD through next-generation sequencing. Methods: Paired DNA (sorted CD66b-granulocytes/skin biopsy) from 102 patients with MPNs or MDS/MPD was subjected to whole exome sequencing on a Illumina HiSeq 2000 platform using Agilent SureSelect kit. Diagnosis included primary myelofibrosis (MF; N=42), essential thrombocythemia (ET; N=28), polycythemia vera (PV; N=12), chronic myelomonocytic leukemia (CMML; N=10), systemic mastocytosis (MS; N=6), MDS/MPD-Unclassified (N=2) and post-MPN AML (N=2). Tumor coverage was 150x and germline coverage was 60x. Somatic variants calls were generated by combining the output of Somatic Sniper (Washington University), Mutect (Broad Institute) and Pindel (Washington University). The combined output of these 3 tools was further filtered by in-house criteria in order to reduce false-positive calls (minimum coverage at both tumor/germline ≥8 reads; fraction of reads supporting alternate allele ≥10% in tumor and ≤10% in germline; ratio of allele fraction tumor:germline >2; excluding mutations seen in SNP databases). All JAK2 and CALR mutations were validated through Sanger sequencing. Validation of other somatic mutations is currently underway. Analysis of driver mutations was made with the Intogen web-based software, using the Oncodrive-FM and Oncodrive-cluster algorithms (www.intogen.org). Significantly mutated genes were considered as those with a q-value of <0.10. Results: We identified a total of 309 somatic mutations in all patients, with each patient having an average of 3 somatic abnormalities, fewer than most solid tumors that have been sequenced so far. Mutations occurred in 166 genes, and 40 of these were recurrently somatically mutated in Ph-negative MPNs. By the Oncodrive-FM algorithm, the following genes were identified as the most significantly mutated driver genes in Ph-negative MPNs and MDS/MPDs (in order of significance): CALR, ASXL1, JAK2, CBL, DNMT3A, U2AF1, TET2, TP53, RUNX1, EZH2, SH2B3 and KIT. By the Oncodrive-cluster algorithm, which considers clustering of mutations at a hotspot, the following genes were significantly mutated: KIT, JAK2, SRSF2 and U2AF1. Somatic mutations were seen in genes that are mutated at a low frequency in Ph-negative MPNs, including ATRX, BCL11A, BCORL1, BIRC5, BRCC3, CSF2RB, CUX1, IRF1, KDM2B, ROS1 and SUZ12. Consistent with the clinical phenotype, 96 patients (94%) had mutations that lead to increased cellular proliferation, either through activation of the JAK-STAT pathway (e.g. JAK2, CALR) or mutations that activated directly or indirectly signaling by receptor tyrosine kinases (e.g. FLT3, KIT, CBL). Besides biological pathways regulating cell proliferation, the most commonly implicated pathways included regulation of DNA methylation (e.g. DNMT3A, TET2), mRNA splicing (e.g. U2AF1, SRSF2) and histone modifications (e.g. ASXL1, EZH2), seen in 27%, 25% and 22% of patients, respectively. Abnormalities in these 3 pathways were more often seen in MF, MDS/MPD and CMML, as compared to PV and ET (65% vs. 20%; p<0.0001). Conclusions: Our study represents one of the largest series of patients with these neoplasms evaluated by whole exome sequencing, and together with the published data helps to delineate the genomic landscape of Ph-negative MPNs and MDS/MPDs. The majority of the most frequent mutations seen in Ph-negative MPNs have already been reported. Nevertheless, there are several low frequency mutations that need to be further studied and functionally validated in vitro and in vivo for a deeper knowledge of the pathophysiology of MPNs. Besides activation of cellular proliferation, abnormalities of DNA methylation, histone modification and mRNA splicing emerge as the most important biological pathways in these disorders. Disclosures No relevant conflicts of interest to declare.
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Shuvaev, Vasily, Irina Martynkevich, Alla Abdulkadyrova, et al. "Ph-Negative Chronic Myeloproliferative Neoplasms – Population Analysis, a Single Center 10-years’ Experience." Blood 124, no. 21 (2014): 5556. http://dx.doi.org/10.1182/blood.v124.21.5556.5556.
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Abstract Objectives and background. Nowadays chronic myeloproliferative neoplasms (MPN) other than chronic myelogenous leukemia undergo renaissance of interest. It results from advances in decryption of molecular mechanisms of pathogenesis and invention of target drugs. Epidemiological information is needed to assess potential effect and additional costs of new diagnostic and therapeutic techniques. The objective of our study was to review experience of MPN diagnostic and treatment in our center for past ten years. Methods. Our institution serves as primary hematological outpatient department for a half of Saint-Petersburg city with about 2 million inhabitants. We reviewed patients' charts to obtain information about incidence, symptoms, diagnostic test results, treatment options and relationship to prognostic factors. Statistical methods included descriptive statistics, nonparametric ANOVA for frequencies comparisons and Kaplan-Meyer method with log-rank test for survival comparisons in Statistica 7.0 package. Results. Since 2004 to 2013 there were 570 newly diagnosed MPN patients (pts) in our center. This group consisted of primary myelofibrosis (PMF) (203 pts; 126 female, 77 male; median age 63 years, range 16-83 years), essential thrombocythemia (ET) (201 pts; 146 female, 55 male; median age 58 years, range 23-78 years), polycythemia vera (PV) (166 pts; 96 female, 70 male; median age 57 years, range 20-85 years). The incidence rates were stable during study period: PMF incidence varied from 0.65 to 1.35 with mean of 1.01 new patient per 100 000 inhabitants per year; ET had incidence from 0.60 to 2.1 with mean of 1.00 and PV had incidence from 0.5 to 1.15 with mean of 0.83. The most prevalent symptoms of disease were: splenomegaly (65.5%), constitutional symptoms (fever, night sweats, weight loss) (31.0%), anemia (36.3%) thrombosis (24.1%) for PMF; fatigue (33.2%), headache and dizziness (25.6%), arthralgia (21.8%), erythromelalgia (15.8%) for ET; plethora (82.5%), headache and dizziness (52.4%), fatigue (31.3%) for PV. JAK2V617F was detected in 49.7% of PMF pts, 57.8% of ET pts and in 97.7% of PV pts. Thrombosis rates according WHO IPSET-thrombosis system risks` groups of ET and PV pts were: low-risk group 3.33% (3/90), intermediate-risk group 11.1% (13/117) and 39.4% (63/160) in high-risk group with highly significant (p<0.0001) differences between risks' groups. There were 169 lethal outcomes in the analysed group (102 PMF; 31 ET; 36 PV). Ten-years overall survival rates were 49.8% in PMF pts, 84.6% in ET pts and 78.3% in PV pts. (fig.1). Overall survival in PMF was significantly influenced by risk stratification as IPSS, DIPSS and DIPSS+. Survival curves according DIPSS+ groups are presented in fig.1. Conclusions. Patients with MPN are presented in substantial number; therefore need much finance for novel therapy introduction. Risk stratification systems has high predictive value. Innovative drugs treatment results should be evaluated in comparison with historical control. Figure1 Overall survival in PMF patients according to DIPPS+ stratification groups. Figure1. Overall survival in PMF patients according to DIPPS+ stratification groups. Disclosures No relevant conflicts of interest to declare.
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Alati, Caterina, Bruno Martino, Antonio Marino, Francesca Ronco, Manuela Priolo, and Francesco Nobile. "Familial Chronic Myeloproliferative Neoplasms." Blood 116, no. 21 (2010): 3078. http://dx.doi.org/10.1182/blood.v116.21.3078.3078.
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Abstract Abstract 3078 Chronic myeloproliferative neoplasms (CMNs) include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). So far limited studies of familial clusters of CMNs have been reported.Familial chronic myeloproliferative neoplasms are defined when in the same pedigree at least two relatives have CMNs. Familial CMNs should be distinguished from inherited disorders with Mendelian transmission, high penetrance and polyclonal haematopoiesis named ‘hereditary erythrocytosis' and ‘hereditary thrombocytosis'. Recently a 5- to 7-fold higher risk of MPN among first-degree relatives of patients with MPNs was reported. These findings support the limited studies suggesting a familial clustering in MPNs. The analysis of mutations of JAK2 and MPL may improve our ability to identify these conditions. In a consecutive series of patients observed in our Institution from January 2000 to June 2010, we found that among 460 patients with sporadic CMNs and 94 Ph1 positive chronic myeloid leukemia (CML), the prevalence of familial cases was 4%.With 22 pedigrees, 44 patients (8%) were identified with two relatives affected. Familial CMNs were 11 PV,14 ET,7 PMF, 5 CML respectively, while sporadic cases were 96 PV,204 ET,115 PMF and with other 45 CMNS not furtherly classified. As far as the distribution of the different CMNs within the familial cluster, We observed that only in 4 of 22 families (18%) all the affected relatives were diagnosed with the same disease (homogeneous pattern: PV one family and ET three families), whereas 14 families exhibited a mixed distribution among PV, ET and PMF. 8 families exhibited CMNs associated with other hematological disease such as chrocic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodisplastic syndrome (MDS). Among this, 6 families presented a first or second degree of relationship of first and second generation. In 10 cases the relatives were brothers, affected by familial CMNs with a prevalence of PV and TE clinical phenotype at diagnosis.According to JAK2 (V617F) mutational status, analyzed in 30 out of 44 patients, 19 patients showed a positivity pattern, while 18 families showed a heterogeneous pattern; they included both JAK2 (V617F) -positive and JAK2 (V617F)-negative patients. Among the 19 patients with JAK2 (V617F) positivity, the distribution of positivity according to the diagnosis was 100% of PV, 45% of ET and 55%of PMF; homozygosity was present only in PV cases. In our series, only two members of the same family were affected by familial CMNs. Finally it should be noted that in our series of familial cases clinical presentation, therapeutic approach and type and severity of complications were comparable to that of sporadic cases. In conclusion, the present study indicates the relevant possibility of familial CMNs, thus suggesting the opportunity of a detailed family history as part of the initial work-up of patients with CMDs; in addition it also suggests the usefulness of an accurate biological study. Disclosures: No relevant conflicts of interest to declare.
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Vinogradova, O. Yu, A. L. Neverova, M. V. Chernikov, et al. "Characteristics of regional epidemiological indicators of chronic myeloproliferative neoplasms." Oncohematology 20, no. 2 (2025): 16–29. https://doi.org/10.17650/1818-8346-2025-20-2-16-29.
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Background. Information on the epidemiological picture of chronic myeloid leukemia (CML) and, especially, Ph– chronic myeloproliferative neoplasm (MPN) in Russia is very scarce, each regional population study is important for obtaining information on the diseases in general.Aim. To analyze the regional epidemiological parameters of the most common MPN over a long period of time (2012–2023).Materials and methods. Clinical and epidemiological, population, retrospective-prospective, observational study of CML and classical Ph– MPN (polycythemia vera, essential thrombocythemia, primary myelofibrosis) was conducted at the Moscow City Hematology Center, Botkin Hospital. The observation period was from January 1, 2012 to December 31, 2023. The research database included data from the medical records of regional patients (Moscow).Results. At the time of analysis, the database contained 2191 patients with CML and 5831 with Ph– MPN observed since 2000. In both cohorts, women prevailed with a ratio of 1:1.1 for CML and 1:1.6 for Ph– MPN. The median age of patients in the overall cohort since 2000 at diagnosis of CML was 55 years (men – 52, women – 57), and of Ph– MPN – 64 years (men – 62, women – 64). During the study period, an increase in the median age and in the proportion of diagnosed CML patients aged 65 years and older were noted, the same was not observed in Ph– MPN. However, an increase in the median age and the proportion of elderly patients was revealed in both general cohorts of CML and Ph– MPN. The registered prevalence of CML and Ph– MPN over a 12-year period increased by 90 % (from 6.0 to 11.4 cases per 100,000 population) and 93 % (from 15.28 to 29.46 cases per 100,000 population), respectively. The high reliability of linear trends indicates a uniform increase in the prevalence of CML and Ph– MPN. The registered annual incidence rate of CML increased over 12 years from 0.74 to 1.13 cases per 100,000 population, and Ph– MPN – from 2.05 to 2.84. An increasing tendency in registered annual mortality from 0.23 to 0.36 per 100,000 population for CML, from 0.87 to 1.04 per 100,000 population for Ph– MPN was observed. Its maximum rates in both cohorts matched with the COVID-19 pandemia period; for Ph– MPN the increase was more pronounced. All over the investigated period, the registered annual morbidity rate always exceeded the registered annual mortality rate. In general, the pandemic did not have a significant impact on the registered epidemiological parameters of both cohorts. In the total CML group, 2-, 5-, 10-year overall survival (OS) was 91, 82, 68 %, in Ph– MPN – 93, 83, 63 %, respectively; the median OS was not achieved in both cohorts. The 5- and 10-year OS for Ph– MPN differed between male and female cohorts: 86 and 67 % versus 79 and 58 %, respectively (p <0.05). In younger (younger than 65 years) patients, 5- and 10-year OS were higher (p <0.001) than in patients aged 65 years and older: 89 and 80 % versus 63 and 35 % in CML, 92 and 80 % versus 73 and 44 % in Ph– MPN, respectively. The median OS in CML and Ph– MPN was not achieved in patients younger than 65 years, and among older patients it was 90 months in CML and 105 months in Ph– MPN.Conclusion. An assessment of CML and Ph– MPN epidemiological indicators dynamics over a 12-year period made it possible to draw a number of conclusions about the population characteristics of each studied cohorts and to identify similar trends and differences in the changes occuring.
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Roszkowska, Anna Maria, Rossana Leanza, Emanuela Aragona, et al. "Retinal Vessel Analysis and Microvascular Abnormalities in Patients with Philadelphia-Negative Chronic Myeloproliferative Neoplasms." Journal of Clinical Medicine 13, no. 8 (2024): 2232. http://dx.doi.org/10.3390/jcm13082232.
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Background: Philadelphia-negative chronic myeloproliferative neoplasms are a group of clonal hematopoietic disorders including polycythemia vera, essential thrombocythemia, and primary myelofi-brosis. These neoplasms are characterized by an increased risk of thrombotic complications. Several studies have highlighted that the study of vessels of the retina offers the opportunity to visualize, in vivo, the damage to microcirculation that is common in various systemic pathologies. Methods: in our study, forty patients underwent an ophthalmological examination, using non-invasive imaging tech-niques, for analyses of their retinal vascularization. The objective was to correlate the findings ob-tained from this study of the retina with different markers of thrombotic risk, to demonstrate the usefulness of studying retinal vessels as a possible new prognostic biomarker of thrombotic risk in patients affected by Philadelphia-negative chronic myeloproliferative neoplasms. Results: retinal imaging demonstrated changes in the microcirculation, with a reduced vascular density of the deep and superficial capillary plexuses with respect to a normal group, and a correlation between retinal changes and blood parameters. Conclusions: additional research will allow us to determine whether retinal changes in individuals with chronic myeloproliferative neoplasms could be predictive of the development of thrombotic events in these subjects.
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Jager, R., and R. Kralovics. "Molecular Pathogenesis of Philadelphia Chromosome Negative Chronic Myeloproliferative Neoplasms." Current Cancer Drug Targets 11, no. 1 (2011): 20–30. http://dx.doi.org/10.2174/156800911793743628.
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Yung, Yammy, Emily Lee, Hiu-Tung Chu, Pui-Kwan Yip, and Harinder Gill. "Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms." International Journal of Molecular Sciences 22, no. 2 (2021): 659. http://dx.doi.org/10.3390/ijms22020659.
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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.
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Yung, Yammy, Emily Lee, Hiu-Tung Chu, Pui-Kwan Yip, and Harinder Gill. "Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms." International Journal of Molecular Sciences 22, no. 2 (2021): 659. http://dx.doi.org/10.3390/ijms22020659.
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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.
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Urosevic, Ivana, Andrija Bogdanovic, and Danijela Lekovic. "Myeloproliferative neoplasms and pregnancy." Medical review 75, Suppl. 1 (2022): 121–26. http://dx.doi.org/10.2298/mpns22s1121u.
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Introduction. The Myeloproliferative Neoplasms are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by increased proliferation of the myeloid lineages in the bone marrow. A particular clinical challenge is presented by certain situations in patients with myeloproliferative Neoplasms, which we do not encounter daily. For this reason, in this paper, we will emphasize the approach to overcoming obstacles in patients with Myeloproliferative Neoplasms in specific settings, like pregnancy. Pregnancy with Philadelphia chromosome-negative Myeloproliferative Neoplasms has been reported to be associated with maternal thrombosis, hemorrhage, and placental dysfunction leading to fetal growth restriction or loss. Thrombocytosis, leucocytosis, high level of hematocrit, activation of Platelets, leucocytes, and circulating pro-thrombotic are connected with the pathogenesis of thrombosis in MPNs With survival expectations similar to age-matched controls and excellent response and worldwide access to tyrosine kinase inhibitors, family planning is increasingly important for many patients with chronic myeloid leukemia. All patients were managed by a multidisciplinary team of physicians with obligatory hematological and gynecologistsobstetrician consultations.
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Sabattini, Elena, Marco Pizzi, Claudio Agostinelli, et al. "Progression in Ph-Chromosome-Negative Myeloproliferative Neoplasms: An Overview on Pathologic Issues and Molecular Determinants." Cancers 13, no. 21 (2021): 5531. http://dx.doi.org/10.3390/cancers13215531.
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Progression in Ph-chromosome-negative myeloproliferative neoplasms (MPN) develops with variable incidence and time sequence in essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These diseases show different clinic-pathologic features and outcomes despite sharing deregulated JAK/STAT signaling due to mutations in either the Janus kinase 2 or myeloproliferative leukemia or CALReticulin genes, which are the primary drivers of the diseases, as well as defined diagnostic criteria and biomarkers in most cases. Progression is defined by the development or worsening of marrow fibrosis or the progressive increase in the marrow blast percentage. Progression is often related to additional genetic aberrations, although some can already be detected during the chronic phase. Detailed scoring systems for clinical usage that are mostly applied in patients with primary myelofibrosis have been defined, and the most recent ones include cytogenetic and molecular parameters with prognostic significance. Additional different clinic-pathologic changes have been reported that may occur during the course of the disease and that are, at present, classified as WHO-defined types of progression, although they likely represent such an event. The present review is meant to provide an updated overview on progression in Ph-chromosome-negative MPN, with a major focus on the pathologic side.
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Guerin, Estelle, Francis Belloc, Gabriel Etienne, Pierre Duffau, Francois-Xavier Mahon, and Eric Lippert. "Reactive Oxygen Species Are Differentially Regulated in Chronic Myeloid Leukemia Versus Philadelphia Negative Myeloproliferative Neoplasms." Blood 112, no. 11 (2008): 4215. http://dx.doi.org/10.1182/blood.v112.11.4215.4215.
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Abstract Deregulation of tyrosine-kinases is a characteristic of most Myeloproliferative Neoplasms (MPN); evolution from chronic phase to acute leukemia depends on the acquisition of additional mutations. Reactive Oxygen Species (ROS), the production of which is increased by tyrosine-kinase activation, can be responsible for additional mutations. The role of ROS in generating genetic aberrations has been mainly studied in BCR-ABL-positive cell lines. Little is known of ROS metabolism in primary cells from CML or Philadelphia-negative MPN (Ph-MPN). After informed consent, cells from blood or bone marrow were obtained from patients diagnosed with CML (12 bone marrow (BM), 8 peripheral blood (PB)), or Ph-MPN (4 Polycythemia Vera, 6 Essential Thrombocythemia, 3 Primary Myelofibroses, 2 atypical CML) and from healthy donors (bone marrow donors) or patients devoid of hematological disease undergoing thoracotomy. Cells were incubated with DCFDA, a fluorogenic marker of ROS production, labelled with an anti-CD45 antibody, stimulated with either the oxidant hydrogen peroxide (H2O2) or the PKC activator Phorbol Myristate Acetate (PMA), and analysed for ROS production by flow cytometry. CD45/SSC gating allowed separate analysis of granulocytes, monocytes or lymphocytes. The basal level of ROS was not higher in CML cells as compared to normal BM or PB leukocytes. It was even significantly lower in CML lymphocytes, either from the BM (2.35 Arbitrary Units vs 8.3 AU, p=5.5 10−5) or PB (2.47 AU vs 7.4 AU, p=3.10−5) and in CML granulocytes from peripheral blood (14 AU vs 45 AU, p =10 −5), but not bone marrow. The ROS levels of Ph-MPN cells were similar or slightly higher than control cells. Upon H2O2 stimulation however, ROS production increased significantly more in CML cells as compared to normal cells (6 fold increase), whatever the cell type (granulocytes, monocytes and lymphocytes) or their origin (PB or BM). In contrast, for Ph-MPN cells, H2O2-stimulated ROS production was close to that of normal cells, with only BM lymphocytes showing ROS generation four fold higher than control BM lymphocytes. After PMA stimulation, which yielded a more modest ROS production than H2O2, CML cells behaved similarly to normal cells, whereas ROS production was four fold higher in Ph-MPN cells, whatever their type and origin. In conclusion, ROS levels at the basal stage are not higher in MPN cells, whether they are Philadelphia positive or negative, as compared to normal cells. Various kinds of stimulation induce different patterns of response, CML cells being more sensitive to oxidants whereas Ph-MPN cells respond more to the cytokine-mimicking agent PMA. These results suggest that the mechanisms of ROS generation and thus of genetic instability are different in CML and Ph-MPN.
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Jelinek, Jaroslav, Yasuhiro Oki, Vazganush Gharibyan, et al. "JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome–negative CML, and megakaryocytic leukemia." Blood 106, no. 10 (2005): 3370–73. http://dx.doi.org/10.1182/blood-2005-05-1800.
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AbstractAn activating 1849G&gt;T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)–negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph+CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G&gt;T mutation is common in Ph– MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.
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Treaba, Diana O., Salwa Khedr, Shamlal Mangray, Cynthia Jackson, Jorge J. Castillo, and Eric S. Winer. "Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature." Case Reports in Hematology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/875039.
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Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML. The small lymphoid aggregates noted in his bone marrow were neoplastic in nature and represented bone marrow involvement by a CD5-negative mantle cell lymphoma (MCL) that presented without any associated lymphadenopathy. We reviewed the English medical literature to identify a single case report of simultaneous association of AML and a MCL in the bone marrow. The unusual association presented here suggests an increase in observer awareness to apparently benign lymphoid aggregates in chronic myeloproliferative neoplasms.
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Джумабаева, Болдукыз Толгонбаевна. "The Role of Leukocytes in the Formation of Neutrophil Extracellular Traps and Thrombosis in Ph-Negative Myeloproliferative Neoplasms: A Literature Review." Клиническая онкогематология 16, no. 3 (2023): 263–67. http://dx.doi.org/10.21320/2500-2139-2023-16-3-263-267.
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Thrombotic complications often cause death in patients with chronic Ph-negative myeloproliferative neoplasms (MPNs). In spite of numerous studies, the pathogenesis of thrombus formation in MPN patients remains unclear. Its mechanism is complex and is determined by many factors. One of the essential phases in thrombogenesis is characterized by the activation of cell mechanisms and formation of neutrophil extracellular traps (NETs). NETs consist of DNA strands, histones, granular proteins and along with pathogen destruction provide an ideal matrix for platelet and clotting mechanism activation.
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Pulido, Mariem, Elena Tuna Aguilar, and Junice Teresita Sosa Romero. "Association of Hyperuricemia with Thrombosis in Philadelphia-Negative Chronic Myeloproliferative Neoplasms." Blood 144, Supplement 1 (2024): 6636. https://doi.org/10.1182/blood-2024-203647.
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INTRODUCTION Elevation of uric acid (UA) in chronic myeloproliferative neoplasms (cMPN) has been attributed to an increase in production by clonal neoplasm cells and a decrease in its excretion due to a decreased glomerular filtration rate (GFR) [1]. A few studies have associated hyperuricemia with a higher risk of thrombosis in cMPN, comparing essential thrombocythemia (ET) and polycythemia vera (PV). Elevated levels of UA have been associated with a higher risk of cardiovascular morbidity and mortality. Thrombosis is a frequently encountered event in cMPN, mainly in polycythemia vera PV and ET; elevated UA could be considered as an independent risk factor regardless of mutational status in cMPN. OBJECTIVES To establish whether hyperuricemia constitutes a risk factor in chronic myeloproliferative neoplasms for thrombotic events compared to other known risk factors. MATERIALS AND METHODS We conducted a retrospective study in patients over 18 years old diagnosed with classic cMPN: PV, ET, and primary myelofibrosis (PMF) from 2015 to 2024 according to the 2022 WHO criteria. Patients with UA levels at diagnosis and prior to treatment initiation for cMPN were included exclusively. Hyperuricemia was defined as UA levels ≥ 7 mg/dL. The time calculated for thrombotic events was from diagnosis until the thrombosis events. We included different types of thromboses as the following: Thromboses in unusual sites: StrokeSplanchnic thrombosis: Budd-Chiari syndrome, portal vein thrombosis, mesenteric thrombosis;Venous thromboses: splanchnic thrombosis and deep vein thrombosis (DVT)Arterial thromboses: acute myocardial infarction and stroke. RESULTS A total of 100 patients with cMPN met the inclusion criteria, female was the predominant gender. 60% were diagnosed with PV (77.6% high risk), 9% with ET (44.4% very-low risk), and 31% with PMF (35.5% intermediate-high risk). The mean age was 55.4 ± 15.7; 47.9 ± 20.2; and 58.5 ± 14.1 years, respectively. 50% of patients had elevated UA levels at diagnosis, mostly in men (62%) and ≥60 years old (64%). Non-significant differences were shown in thrombotic events between patients with normal UA levels and those with hyperuricemia. Table 1 shows the main baseline characteristics of the population with myeloproliferative neoplasms based on the presence of hyperuricemia. In our Cox model shown in Table 2 PV and ET presented a higher risk of thrombosis compared to PMF. Hyperuricemia at diagnosis was not associated with a higher risk of thrombotic events. CONCLUSIONS No study has demonstrated hyperuricemia as a risk factor for thrombosis among the three classic cMPN to date. The studies known in the literature that provide an analysis of hyperuricemia association with higher risks of thrombosis and death were made between PV and ET, or searching for individual outcomes in PMF. However in our analysis, we aimed to compare the relationship of hyperuricemia with thrombosis risk among the three types of cMPN, where a non-significant difference was observed in thrombotic events between those with hyperuricemia compared to those with normal UA levels. There is an unmet need to explore other risk factors that would influence the high rate of thrombosis present in these neoplasms in addition to the already known risk factors.
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Holmström, Morten Orebo, Hans Carl Hasselbalch, and Mads Hald Andersen. "Cancer Immune Therapy for Philadelphia Chromosome-Negative Chronic Myeloproliferative Neoplasms." Cancers 12, no. 7 (2020): 1763. http://dx.doi.org/10.3390/cancers12071763.
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Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN.
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Barcelos, Michelle Maccarini, and Maria Cláudia Santos-Silva. "Molecular approach to diagnose BCR/ABL negative chronic myeloproliferative neoplasms." Revista Brasileira de Hematologia e Hemoterapia 33, no. 4 (2011): 290–96. http://dx.doi.org/10.5581/1516-8484.20110079.
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Виноградова, О. Ю., Анна Леонидовна Неверова, М. М. Панкрашкина, et al. "Paroxysmal Nocturnal Hemoglobinuria and Primary Myelofibrosis as an Extremely Rare Combination of Clonal Hematological Diseases: A Literature Review and Two Clinical Case Reports." Clinical Oncohematology 17, no. 2 (2024): 195–203. http://dx.doi.org/10.21320/2500-2139-2024-17-2-195-203.
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The combinations of paroxysmal nocturnal hemoglobinuria (PNH) and chronic myeloproliferative neoplasms (CMPNs) are extremely rare. All of them refer to clonal hematological diseases and are characterized by high thrombosis risk, which most commonly causes death. This paper provides literature data on 38 combined cases of PNH and Ph-negative/Ph-positive CMPNs mainly in the “case report” format, taken from 22 sources published in 1970–2022. Additionally, the paper reports personal experience with 2 combined cases of PNH and primary myelofibrosis (PMF/PNH) from the archive of the Moscow Municipal Center for Hematology (SP Botkin City Clinical Hospital).
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Sadigh, Sam, Robert P. Hasserjian, and Gabriela Hobbs. "Distinguishing atypical chronic myeloid leukemia from other Philadelphia-negative chronic myeloproliferative neoplasms." Current Opinion in Hematology 27, no. 2 (2020): 122–27. http://dx.doi.org/10.1097/moh.0000000000000565.
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Christensen, Alexander Sidelmann, Jonas Bech Møller, and Hans Carl Hasselbalch. "Chronic kidney disease in patients with the Philadelphia-negative chronic myeloproliferative neoplasms." Leukemia Research 38, no. 4 (2014): 490–95. http://dx.doi.org/10.1016/j.leukres.2014.01.014.
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Lasho, Terra, Ayalew Tefferi, Alessandro M. Vannucchi, et al. "LNK Mutation Studies In Chronic- and Blast-Phase Myeloproliferative Neoplasms and JAK2 Mutation-Negative Erythrocytosis." Blood 116, no. 21 (2010): 4105. http://dx.doi.org/10.1182/blood.v116.21.4105.4105.
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Abstract Abstract 4105 Background: JAK2 mutations are found in approximately 99% of patients with polycythemia vera (PV) and 60% of those with essential thrombocythemia (ET) or primary myelofibrosis (PMF). It is currently assumed that other mutations relevant to JAK signaling contribute to the pathogenesis of JAK2 mutation-negative myeloproliferative neoplasms (MPN). The same might hold true for some cases of “idiopathic erythrocytosis” associated with subnormal serum erythropoietin level (sEpo). LNK is a plasma membrane-bound adaptor protein whose function includes inhibition of wild-type and mutant JAK2 phosphorylation. LNK exon 2 mutations were recently described in two patients with JAK2V617F-negative ET or PMF. Both mutations involved the LNK pleckstrin homology (PH) domain; one was a 5 base-pair deletion and missense mutation leading to a premature stop codon (603_607delGCGCT; 613C>G) and the other a missense mutation (622G>C; glutamic acid to glutamine substitution; E208Q). Objectives: i) To estimate the prevalence of LNK mutations in chronic and blast phase MPN ii) To determine if LNK mutations are mutually exclusive of other MPN-associated mutations iii) To test the hypothesis that LNK mutations might contribute to the pathogenesis of JAK2 mutation-negative PV or otherwise unexplained erythrocytosis Methods: LNK mutation analysis was performed on bone marrow or blood cells using modified primers for amplifying the SH2 and PH domains, using previously published methods (Oh et al. Blood First Edition Paper, prepublished online April 19, 2010; DOI 10.1182/blood-2010-02-270108). Results: LNK mutation studies were performed in 172 patients; paired chronic-blast phase samples were analyzed in 26 cases. Diagnoses in the 172 study patients were as follows: 78 chronic-phase MPN (39 JAK2V617F-positive PV, 25 PMF and 14 ET) enriched for TET2, IDH, JAK2V617F, or MPL mutations, 61 blast-phase MPN (41 blast-phase PMF, 11 blast-phase PV and 9 blast-phase ET), 25 JAK2V617F-negative PV and 8 “unexplained erythrocytosis” associated with subnormal sEpo and negative for Epo receptor (EPOR) mutations. Ten novel heterozygous LNK mutations, all but one affecting exon 2 in the PH domain, were identified: 6 missense mutations involving codons 215, 220, 223, 229 and 234, one nonsense mutation involving codon 208 (622G>T leading to glutamic acid to a stop codon substitution; E208X), one synonymous mutation involving codon 208, and 2 deletion mutations involving exon 2 (685-691_delGGCCCCG) or exon 5 (955_delA). LNK mutations were most frequent in blast-phase MPN, occurring in 6 (9.8%) of the 61 informative patients; chronic-phase sample analysis in 4 of these revealed the same mutation in only one case. Mutant LNK was detected in chronic-phase samples only in 2 additional patients with blast-phase MPN. Among the 8 LNK-mutated blast-phase MPN cases, 7 had blast-phase PMF. The clinical phenotype in the remaining 2 LNK-mutated patients was that of an isolated erythrocytosis without overt features of PV. JAK2V617F was documented in 3 and IDHR140Q in 1 LNK-mutated patients. Conclusions: LNK mutations i) target an exon 2 ‘hot spot' in the PH domain spanning residues E208-D234, ii) might be most prevalent in blast-phase PMF iii) are not mutually exclusive of JAK2 or IDH mutations and iv) might be part of the “missing link” in the pathogenesis of JAK2 mutation-negative “idiopathic” erythrocytosis. Disclosures: No relevant conflicts of interest to declare.
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Torres, Dania G., Jhemerson Paes, Allyson G. da Costa, et al. "JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms." Biomolecules 12, no. 2 (2022): 291. http://dx.doi.org/10.3390/biom12020291.
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The JAK2V617F variant constitutes a genetic alteration of higher frequency in BCR/ABL1 negative chronic myeloproliferative neoplasms, which is caused by a substitution of a G ˃ T at position 1849 and results in the substitution of valine with phenylalanine at codon 617 of the polypeptide chain. Clinical, morphological and molecular genetic features define the diagnosis criteria of polycythemia vera, essential thrombocythemia and primary myelofibrosis. Currently, JAK2V617F is associated with clonal hematopoiesis, genomic instability, dysregulations in hemostasis and immune response. JAK2V617F clones induce an inflammatory immune response and lead to a process of immunothrombosis. Recent research has shown great interest in trying to understand the mechanisms associated with JAK2V617F signaling and activation of cellular and molecular responses that progressively contribute to the development of inflammatory and vascular conditions in association with chronic myeloproliferative neoplasms. Thus, the aim of this review is to describe the main genetic, hematological and immunological findings that are linked to JAK2 variant signaling in chronic myeloproliferative neoplasms.
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Masselli, Elena, Giulia Pozzi, Giuliana Gobbi, et al. "Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants." Cells 9, no. 9 (2020): 2136. http://dx.doi.org/10.3390/cells9092136.
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Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.
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Swaminathan, Mahesh, Keyur P. Patel, Julie Huynh-Lu, et al. "Unique Case of Myeloproliferative Neoplasm with Two Rare Clonal Abnormalities: Rare JAK2 Exon 12 Mutation and Rare e14a3 (b3a3) BCR/ABL Fusion Transcript." Acta Haematologica 141, no. 1 (2018): 23–27. http://dx.doi.org/10.1159/000494427.
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Myeloproliferative neoplasms (MPNs) are clonal disorders divided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) or Ph chromosome-negative MPNs. Co-occurrence of these disease entities is very rare and typically involves presence of common p190 or p210 BCR/ABL fusion transcript (responsible for CML) along with JAK2V617F mutation (most common driver mutation in Ph-negative MPNs). Because of the rarity of such cases, it is not clear if the outcomes are any different in these patients. In this article, we report a unique patient with polycythemia vera driven by a rare complex in-frame deletion-insertion mutation in JAK2 exon 12, and CML driven by uncommon p210 e14a3 (b3a3) BCR/ABL fusion transcript. We describe clinical and laboratory features, bone marrow pathology, treatment, and overall outcome.
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Cahill, Kirk, Anand Ashwin Patel, Hongtao Liu, et al. "Outcomes of IDH-Mutated Advanced Phase Ph-Negative Myeloproliferative Neoplasms Treated with IDH Inhibitors." Blood 134, Supplement_1 (2019): 4176. http://dx.doi.org/10.1182/blood-2019-122380.
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Background: Myeloproliferative neoplasms (MPNs) that progress to an accelerated phase (AP) or blast phase (BP) have poor outcomes with a median survival of 3 to 5 months. Approximately 20% of MPN-BP patients have a pathogenic mutation in IDH1 or IDH2. Ivosidenib and enasidenib, inhibitors of the IDH1 and IDH2 mutant enzymes respectively, provide a new treatment approach for high-risk IDH-mutated acute myeloid leukemia (AML). There are limited clinical trial data and real-world experience with IDH inhibitors in MPN-AP/BP. We hypothesized that patients with IDH-mutated MPN-AP/BP may benefit from IDH inhibitor therapy. We performed a single institution retrospective analysis of patients with AML arising from a prior chronic myeloid neoplasm treated with an IDH inhibitor and evaluated outcomes of the MPN-AP/BP patients. Methods: Retrospective chart review was done to identify patients with IDH1/2-mutated MPN AP/BP, AML arising from myelodysplastic syndrome (MDS-AML), or AML arising from CMML (CMML-AML), that were treated with ivosidenib or enasidenib from 1/1/2009-5/14/2019. Response was assessed using both the 2003 International Working Group AML (2003 IWG AML) criteria and 2017 European LeukemiaNet (ELN) criteria. For the MPN-AP/BP patients, response was also assessed using the 2012 Post-MPN AML Consortium (2012 MPN-BP) criteria (Mascarenhas et al. Leuk Res 2012). Overall survival from initiation of IDH inhibitor therapy and adverse event data were collected. Results: There were 96 patients with IDH1 or IDH2 mutations identified by analysis of Next Generation Sequencing (NGS) data. 15 of these patients underwent treatment with an IDH inhibitor and had an antecedent chronic myeloid neoplasm: 7 MPN-BP, 1 MPN-AP, 5 MDS-AML, and 2 CMML-AML. Median age was 69 years old with a median Charlson Comorbidity Index of 6. ELN risk criteria could be assessed in 13/15 patients; of those, 54% were adverse-risk. 13 IDH2 mutated patients received enasidenib as monotherapy (n=12) or combined with azacitidine (n=1). 2 IDH1-mutated patients received ivosidenib as monotherapy (n=1) or combined with azacitidine (n=1). Of the 8 MPN-AP/BP patients, 6 received IDH inhibitor therapy in the front-line setting. Of the 7 patients with MDS-AML or CMML-AML, only 2 patients received IDH inhibitor therapy in the frontline setting. The overall response rate (ORR) to IDH inhibitor therapy for the 15 patients was 40% using both the 2003 IWG AML criteria and the 2017 ELN criteria. In the 8 patients with MPN-AP/BP, the ORR was 37.5% using both the 2003 IWG AML response criteria and the 2017 ELN criteria and was 75% when using the 2012 MPN-BP response criteria (Table 1). Median overall survival was not reached for the 3 MPN-BP patients reclassified as responders using 2012 MPN-BP criteria with median follow-up at time of data lock being 431 days (range, 67-1218+). Median duration of IDH inhibitor therapy in the whole 15 patient cohort was 126 days (range, 14-1218+) and 258 days (14-1218+) for MPN-BP patients. Median follow-up at time of data lock was 151 days for all patients and 272 days for MPN-BP patients. Within the MPN-AP/BP cohort, 3 are still on therapy at this time, 2 had stopped due to progression of disease, and 3 had stopped due to an adverse event or clinical deterioration (Figure 1). Median overall survival for all patients after initiation of IDH inhibitor therapy was 235 days (Figure 2). Median survival for patients with MPN-AP/BP (n=8) was not reached compared to 193 days for the 7 patients with MDS-AML or CMML-AML. The incidence of Grade 3 or greater adverse events was similar to the known AE profile of these agents. NGS analysis at time of progression to AML/accelerated phase identified JAK2 and SRSF2 mutations as the most frequent co-mutations (Table 2). Conclusions: Treatment with IDH inhibitor therapy in IDH-mutated MPN-AP/BP patients holds promise as a means of inducing durable responses that extend beyond historical survival data for MPN-BP. In addition, utilization of the 2012 MPN-BP criteria to assess response in this patient population can provide better insight into the benefit of this treatment strategy. Our single institutional experience merits confirmation in a larger group of patients with IDH1/2-mutated MPN-AP/BP. Disclosures Liu: Agios: Honoraria; Novartis: Other: PI of clinical trial; Arog: Other: PI of clinical trial; Karyopharm: Research Funding; BMS: Research Funding. Thirman:Celgene: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; Up to Date: Honoraria; Gilead: Research Funding; Janssen: Consultancy; Astra Zeneca: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy, Research Funding. Artz:Miltenyi: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Segal:Astra Zeneca: Consultancy; Merck: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Research Funding. Odenike:Agios: Research Funding; CTI/Baxalta: Research Funding; Gilead Sciences: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Oncotherapy: Research Funding; Astex Pharmaceuticals: Research Funding; Astra Zeneca: Research Funding; Janssen Oncology: Research Funding; NS Pharma: Research Funding. OffLabel Disclosure: We discuss the use of the IDH inhibitors ivosidenib and enasidenib in treatment of advanced-phase Ph-negative myeloproliferative neoplasms. Ivosidenib is currently approved for use in the frontline setting in IDH1-mutated AML patients >75 years old or with comorbidities precluding the use of intensive induction therapy. Ivosidenib is also approved in the relapsed/refractory setting for IDH1-mutated AML. Enasidenib is approved in the relapsed/refractory setting for IDH2-mutated AML.
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Stuckey, Ruth, Cristina Bilbao-Sieyro, Adrián Segura-Díaz, and María Teresa Gómez-Casares. "Molecular Studies for the Early Detection of Philadelphia-Negative Myeloproliferative Neoplasms." International Journal of Molecular Sciences 24, no. 16 (2023): 12700. http://dx.doi.org/10.3390/ijms241612700.
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JAK2 V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). JAK2 mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) in otherwise “healthy” individuals. However, the period between mutation acquisition and MPN diagnosis (known as latency) varies widely between individuals, with JAK2 mutations detectable several decades before diagnosis and even from birth in some individuals. Here, we will review the current evidence on the biological factors, such as additional mutations and chronic inflammation, which influence clonal expansion and may determine why some JAK2-mutated individuals will progress to an overt neoplasm during their lifetime while others will not. We will also introduce several germline variants that predispose individuals to CHIP (as well as MPN) identified from genome-wide association studies. Finally, we will explore possible mutation screening or interventions that could help to minimize MPN-associated cardiovascular complications or even delay malignant progression.
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Rampal, Raajit K., Sean M. Devlin, Jay P. Patel, et al. "Integrated Genetic Profiling Of JAK2 Wildtype Chronic-Phase Myeloproliferative Neoplasms." Blood 122, no. 21 (2013): 1588. http://dx.doi.org/10.1182/blood.v122.21.1588.1588.
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Abstract Background The Myeloproliferative Neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF) are clonal hematopoietic disorders. JAK2V617F mutations are observed in approximately 90-95% of PV cases, but only 40-50% of ET and PMF cases. Although JAK2 exon 12 and LNK mutations are observed in the majority of JAK2V617F-negative PV patients, candidate gene and exome sequencing studies to date have not identified activating oncogenes in the majority of JAK2V617F-negative ET/PMF patients. Thus, further genetic investigations are needed to define the mutational architecture of these JAK2 wildtype MPNs in order to gain insight into the biology of these diseases, the clinical implications of genetic events that do occur, and the elucidation of potential therapeutic targets. Aims To characterize the spectrum of genetic alterations in JAK2 wildtype chronic-phase myeloproliferative neoplasms. Methods We identified 32 patients with a confirmed diagnosis of an MPN (per 2008 WHO criteria), including MF, PV and ET, who were negative for JAK2V617F using a CLIA-certified allele specific assay for the JAK2 disease allele. Genomic DNA and total RNA was isolated from formalin fixed paraffin embedded (FFPE) tissue, blood and bone marrow aspirates. Adaptor ligated sequencing libraries were captured by solution hybridization using two custom baitsets targeting 374 cancer-related genes and 24 genes frequently rearranged for DNA-seq, and 258 genes frequently rearranged for RNA-seq. All captured libraries were sequenced to high depth (Illumina HiSeq), averaging >590X for DNA and >20,000,000 total pairs for RNA, to enable the sensitive and specific detection of genomic alterations. Results High coverage sequencing allowed us to identify JAK2V617F mutations in two patients (allele burden 3-5%) that were below the limit of detection of the CLIA assay. The most common mutations observed in JAK2V617F-negative MPN were in ASXL1 (22% of patients) and in TET2 (9%). Taken together, mutations in known epigenetic modifiers (ASXL1, TET2, DNMT3A, EZH2, MLL) were observed in 43% of samples, including a MLL-PTD mutation in one patient with PMF. We identified mutations in spliceosome components (SRSF2, U2AF1), in a subset of patients, consistent with previous reports, and in each case mutations in spliceosome components were mutually exclusive. We identified mutations in the JAK-STAT pathway (MPL, TYK2) and the RAS pathway components (KRAS, NF1) in 9% of this patient cohort, suggesting that there are alternate disease alleles that activate signaling in JAK2V617F-negative MPN. RNA-sequencing identified a ETV6-ABL1 fusion in one patient, and we identified amplification of PIK3CA in one patient in our cohort; these data suggest fusion genes and amplifications activate signaling in a subset of patients with JAK2V617F-negative MPN. We also identified novel mutations in MPN patients which have not been reported to date, including mutations in DNA repair genes (ATM and BRCA) in 25% of cases and mutations in the Notch signaling pathway (NOTCH1-4) in 31% of cases. The functional implications of these novel mutations remain to be elucidated. In univariate analysis, ASXL1 mutations were found to associate with impaired overall survival (Figure 1, p=0.049). These findings are consistent with data demonstrating an impaired survival in patients with MDS and PMF, and suggest that ASXL1 mutations represent an important biomarker for adverse outcome in JAK2V617F-negative MPN. Conclusions These data demonstrate that the mutational spectra of JAK2V617F-negative MPN includes genes implicated in epigenetic regulation, novel mutations which activate gene signaling, and fusion genes/copy number alterations which provide a novel mechanism of oncogenic activation not previously reported in MPN. ASXL1 mutations occur frequently in JAK2 wildtype Philadelphia-Chromosome negative MPNs, and are associated with impaired overall survival. Collectively, these findings support the importance of ASXL1 mutations in predicting outcome in JAK2V617F-negative MPN, demonstrate that mutations in signaling effectors and in epigenetic regulators are common in MPN, and illustrate the genetic heterogeneity of JAK2V617F-negative MPN. Disclosures: Rampal: Foundation Medicine: Consultancy. Levine:Foundation Medicine, Inc: Consultancy.
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Hasselbalch, Hans Carl, Jean-Jacques Kiladjian, and Richard T. Silver. "Interferon Alfa in the Treatment of Philadelphia-Negative Chronic Myeloproliferative Neoplasms." Journal of Clinical Oncology 29, no. 18 (2011): e564-e565. http://dx.doi.org/10.1200/jco.2011.35.6238.
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Sørensen, Anders Lindholm, and Hans Carl Hasselbalch. "Antecedent cardiovascular disease and autoimmunity in Philadelphia-negative chronic myeloproliferative neoplasms." Leukemia Research 41 (February 2016): 27–35. http://dx.doi.org/10.1016/j.leukres.2015.11.017.
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Caramazza, Domenica, Clementina Caracciolo, Rita Barone, et al. "Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms." Annals of Hematology 88, no. 10 (2009): 967–71. http://dx.doi.org/10.1007/s00277-009-0706-x.
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Skov, Vibe, Mads Thomassen, Lasse Kjær, Thomas Stauffer Larsen, Torben A. Kruse, and Hans Hasselbalch. "Highly Deregulated Fibulins in Patients with Philadelphia-Negative Chronic Myeloproliferative Neoplasms." Blood 134, Supplement_1 (2019): 5396. http://dx.doi.org/10.1182/blood-2019-130560.
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Introduction The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) develop in a biological continuum from the early cancer stages (ET/PV) to the advanced myelofibrosis stage characterized by huge splenomegaly, bone marrow failure and -fibrosis. Importantly, bone marrow fibrosis also increases from the early stages with reticulin fibrosis only and later deposition of mature collagen as well. Fibulins are glycoproteins that are important constituents of the extracellular matrix (ECM). Thus, fibulins have been shown to modulate cell morphology, growth, adhesion and motility. Dysregulation of fibulins has been reported in several cancers. In addition, upregulation of fibulins and elevated circulating fibulins have been reported in diseases - other than cancers -, in which chronic inflammation is an important pathogenetic factor, such as cardiovascular diseases. Thus, deregulated fibulins have been described in patients with type 2 diabetes mellitus. Herein, using whole blood gene expression profiling, we for the first time report deregulated fibulins in patients with MPNs. Aim To detect if genes associated with pre-atherosclerotic changes in type II diabetes are deregulated in patients with MPNs. Material and methods Gene expression microarrays were applied to generate gene expression profiles of whole blood from control subjects (n=21) and patients with ET (n=19), PV (n=41), and PMF (n=9). Total RNA was purified, amplified to biotin-labeled aRNA and hybridized to microarray chips. The statistical software R was applied to perform initial data processing and statistical analysis of gene expression changes between patients and control subjects. An FDR <0.05 was considered significant. Results We identified 23,657, 25,567, and 17,417 probe sets which were significantly differentially expressed between controls and patients with ET, PV, and PMF, respectively (FDR < 0.05). We focused upon the top 15 upregulated genes from a previous gene expression microarray study performed on arterial tissue from patients with type 2 diabetes compared to non-diabetic patients undergoing artery bypass graft surgery. Several of these genes were significantly deregulated in patients with MPNs (Table 1). In patients with ET, FBLN1, FBLN2,FAM107A, IGF2, MEG3, and ELN were significantly upregulated and ZFP36L2 were significantly downregulated. In patients with PV, FBLN1, FBLN2, ELN, LEPR, FAM107A, IGF2, CRISPLD2, and MEG3 were significantly upregulated and ZFP36L2 and SERPINF1 were significantly downregulated. In patients with PMF, MEG3, LEPR, FBLN1, FAM107A, ELN, IGF2, and VWF were significantly upregulated and ZFP36L2 and SERPINF1 were significantly downregulated. Discussion and conclusions Fibulins regulate several cellular functions including tissue homeostasis and remodeling after injury, angiogenesis, and tumorigenesis. Thus, fibulins have been reported to be upregulated in several cancer types, in which deregulated fibulins have been associated with cancer invasiveness and disease progression. We have for the first time shown that fibulins are also highly deregulated in patients with MPNs. The significance of our findings is presently unknown but since interactions between fibulins and transforming growth factor (TGFbeta) have been demonstrated, upregulated fibulins may enhance the capacities of TGFbeta, which shares several of the regulatory functions excerted by fibulins. In the context of chronic inflammation being a driving force for MPN development during the biological continuum from early cancer stages to the advanced myelofibrosis stage and chronic inflammation likely also accelerates the development of atherosclerosis in MPNs, it is highly intriguing to note that fibulins are also elevated in arteries from patients with type 2 diabetes mellitus. Thus, upregulated fibulins in blood cells may actually indirectly reflect ongoing matrix modelling during atherosclerosis development, including remodeling and turnover of basement membranes in the inflamed endothelium. In conclusion, highly deregulated fibulins have been demonstrated in circulating blood cells by whole blood gene expression profiling. Further studies are needed to assess the significance of our findings in terms of potential associations to modelling of ECM in the bone marrow and during development of atherosclerosis in MPNs. Disclosures Hasselbalch: Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board.
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Oh, Stephen T., Jacob M. Zahn, Carol D. Jones, et al. "Identification of Novel LNK Mutations In Patients with Chronic Myeloproliferative Neoplasms and Related Disorders." Blood 116, no. 21 (2010): 315. http://dx.doi.org/10.1182/blood.v116.21.315.315.
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Abstract Abstract 315 Introduction: Dysregulated JAK-STAT signaling in chronic myeloproliferative neoplasms (MPNs) has primarily been attributed to activating mutations in tyrosine kinases. However, JAK-STAT activation can be demonstrated in some patients lacking JAK2 or MPL mutations, suggesting alteration of other regulatory elements in this pathway. One regulator of JAK-STAT signaling is LNK (SH2B3), an adapter protein that contains a proline-rich N-terminal dimerization domain (Pro/DD), a pleckstrin homology (PH) domain (plasma membrane localization), and an SH2 domain. LNK binds to cytokine receptors (e.g. MPL, EPOR) and JAK2 via its SH2 domain, inhibiting downstream STAT activation and providing critical negative feedback regulation. LNK-/- mice exhibit features consistent with an MPN phenotype. We recently reported the first human disease-related LNK mutations in two JAK2 V617F-negative MPN patients (Oh et al, Blood, Aug 12, 2010). One patient with primary myelofibrosis (PMF) exhibited a 5 base-pair (bp) deletion and missense mutation (DEL) leading to a premature stop codon and loss of the PH and SH2 domains. A second patient with essential thrombocythemia (ET) was found to have a missense mutation (E208Q) in the PH domain. Both mutations conferred aberrant JAK-STAT signaling in cell lines and primary patient samples, indicating that loss of LNK negative feedback regulation contributes to MPN pathogenesis. We now report the results of a comprehensive screen of a large cohort of MPN, overlap myelodysplastic syndrome (MDS)/MPN, and post-MDS/MPN acute myeloid leukemia (AML) patients for LNK mutations. Methods: A total of 341 samples were sequenced (Table 1; polycythemia vera (PV)=34, erythrocytosis=7, ET=61, PMF=75, post-PV/ET MF=25, MPN-U=7, chronic myelomonocytic leukemia (CMML)=71, juvenile myelomonocytic leukemia=20, MDS/MPN=8, MDS with fibrosis=2, refractory anemia with ring sideroblasts and thrombocytosis=4, idiopathic hypereosinophilic syndrome/chronic eosinophilic leukemia=4, systemic mastocytosis=4, and post MDS/MPN AML=19). A deep sequencing approach (Illumina multiplexing system) was used to evaluate 84 samples, in which all exons of LNK were sequenced. For the remainder of the samples, direct sequencing was performed on exon 2, the region containing the previously reported DEL and E208Q mutations. Results: After excluding variants previously reported in SNP databases, a total of 11/341 (3.2%) patients were found to have non-synonymous mutations, including 3/61 (4.9%) ET, 3/75 (4.0%) PMF, and 5/71 (7.0%) CMML patients (Table 1). Each of the mutations localized to exon 2 of LNK, implicating this region as a possible mutational hotspot. This included the aforementioned patients with the DEL and E208Q mutations, which were confirmed by deep sequencing. In two other patients, sequencing of DNA from cultured skin fibroblasts DNA indicated that the mutations were germline. For the remaining seven patients, germline analysis is currently ongoing. In one patient with CMML, a 1 bp deletion leading to a frameshift and premature stop codon was identified (Q72fs). This mutation localized to the Pro/DD, likely resulting in a complete loss of LNK function. Interestingly, this patient who is wild type for the JAK2 and RAS genes, also carries a heterozygous CBL mutation (C396Y), suggesting that LNK and CBL mutations may have cooperative effects. Four patients (one with PMF, three with CMML) were found to have a missense mutation (S186I) at a highly conserved residue in the Pro/DD. The previously reported E208Q mutation was also found in one patient with ET and one patient with CMML. None of the 81 patients known to be JAK2 V617F-positive exhibited somatic LNK mutations, suggesting that LNK mutations may provide an alternative basis for JAK-STAT activation in the absence of JAK2 V617F. Conclusion: Missense and deletion mutations of the LNK gene occur at a low frequency in MPNs and MDS/MPNs and segregate predominantly in exon 2. Further analysis of post-MPN AML samples (represented at a low frequency in the current cohort) and other subtypes of acute and chronic myeloid malignancies is warranted to better characterize the disease spectrum of LNK mutations and whether they are mutually exclusive of JAK2 V617F. We are currently investigating whether loss of negative feedback regulation of JAK-STAT signaling is related to haploinsufficiency of LNK or dominant negative effects of the mutant protein. Disclosures: No relevant conflicts of interest to declare.
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Kiem, Dominik, Sandro Wagner, Teresa Magnes, Alexander Egle, Richard Greil, and Thomas Melchardt. "The Role of Neutrophilic Granulocytes in Philadelphia Chromosome Negative Myeloproliferative Neoplasms." International Journal of Molecular Sciences 22, no. 17 (2021): 9555. http://dx.doi.org/10.3390/ijms22179555.
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Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in JAK2, MPL, or CALR, with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.
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Svidnicki, Maria Carolina Costa Melo, Paula De Melo Campos, Moisés Alves Ferreira Filho, et al. "Mutations in Triple-Negative Patients with Myeloproliferative Neoplasms." Blood 134, Supplement_1 (2019): 5395. http://dx.doi.org/10.1182/blood-2019-128764.
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Background Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). JAK2, MPL, and CALR mutations are considered as "driver mutations" and are directly implicated in the disease pathogenesis by activation of JAK/STAT signaling. However, some patients do not harbor any of these mutations. Since such triple-negative MPNs are very rare, no specific molecular markers were established to use for a precise differential diagnosis yet. So far, the introduction of next generation sequencing (NGS) technologies in research of myeloid neoplasms has provided valuable contributions on the identification of new molecular biomarkers, establishing more accurate risk rating and selection of more specific therapeutic interventions. This study aimed to identify, through targeted deep sequencing, specific genetic variants in patients with triple-negative MPNs. Methods We performed NGS targeted sequencing in 18 Brazilian triple-negative patients (11 MF and 7 ET). The median age at diagnosis was 64 years for primary myelofibrosis (range 42-78), and 52 years for essential thrombocythemia (range 19-79). In 14 cases, we used the Illumina TruSight Myeloid Panel covering 54 genes and in 4 cases we used a custom Sure Select Agilent panel containing more than 300 genes previously reported to be related to myeloid neoplasm. The inclusion criteria for variant filtering was quality score>30, read count>50, minor allele frequency<0.05, frameshift, nonsense, splice site and 5`UTR variants, and missense variants described as deleterious for at least three prediction softwares. Results Possible pathogenic mutations were identified in 33 genes by Illumina and/or Agilent panels. Frameshift/nonsense or missense variants previously described as pathogenic correspond to 11 variants (Table 1). Out of these, mutations in TET2 were the most frequently identified (in 9/18 (50%) of the cases). In three MF patients with TET2 mutations no other considered pathogenic mutation was identified, indicating a possible role of TET2 as a driver gene. According to previous reports, the frequency of TET2 mutations in triple-negative MPNs patients were only 7%. Phenotypically, in our triple-negative MPNs, 6/11 (54.5%) MF and 3/7 (42.9%) ET patients harbored TET2 mutations. Clinically, the adverse prognostic impact of TET2 mutations in MPN had not been consistently shown by previous studies. In addition, mutations in SF3B1, CEBPA, and KMT2A genes were the second most frequent ones detected in 2/18 each (11%) of the patients, some of which were concomitant with TET2 mutations, suggesting additional clonal advantage due to these genetic events. Other potentially pathogenic variants were also detected is genes that have been reported to be related to other myeloid neoplasms (KMT2A, CDKN2A, TERT, DIS3, ZFPM1, PCDHA8, SAMD9, SAMD9L, DCLRE1C,ERBB3, SDHA, PCDHA6, SVEP1, MAP2K1 and EP300). Conclusions We have characterized the genomic alterations in 18 Brazilian patients with MPN triple-negative for either JAK2, CALR or MPL main mutations. Using a sensitive NGS platform, we identified significantly more frequent mutations in TET2 gene (in as many as a half of the cases) compared to JAK2, MPL, CALR mutation-positive MPN cases. We also uncovered mutations in genes not previously related with in MPN. Our novel findings call for further studies validating the frequencies, biological significance, and prognostic impacts of somatic mutations in triple-negative MPNs. Disclosures Ogawa: Qiagen Corporation: Patents & Royalties; RegCell Corporation: Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; Asahi Genomics: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding.
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Мисюрин, В. А., А. В. Мисюрин, Л. А. Кесаева та ін. "Новые маркеры прогрессирования хронического миелолейкоза". Clinical Oncohematology 7, № 2 (2014): 206–12. https://doi.org/10.21320/2500-2139-2014-7-2-206-212.
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In the contrast to Ph’-negative chronic myeloproliferative disorders (cMPD), chronic myelogenous leukemia (CML) is prone to rather early transformation into the later stage disease, known as the acceleration phase (AP) and blast crisis (BC). Myeloproliferative disorders are termed myeloproliferative neoplasms in the WHO classification, 2008. Molecular mechanisms underlying CML progression are unclear and still being studied. Recently, it was shown that progression of some malignancies was associated with activation and hyperexpression of some genes from the cancer-testis (CT) family. In this study, we evaluated the gene expression profile of CT genes (GAGE1, NY-ESO-1, MAGEA1, SCP1, SEMG1, SPANXA1, SSX1 and PRAME) in the blood of patients with initially diagnosed cMPD, as well as in the blood and bone marrow of CML patients in CP, AP and BC. It was found that activation of these eight CT genes expression was strongly correlated with CML progression to AP and BP. These data suggest that at least some of CT genes can be involved in CML evolution towards the terminal phases. Expression of these genes can be used as an early molecular predictor of CML progression to AP and BC.
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Giraldo-Rincon, Ana Isabel, Sara Naranjo Molina, Natalia Gomez-Lopera, et al. "JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms." Colombia Medica 54, no. 3 (2023): e2035353. http://dx.doi.org/10.25100/cm.v54i3.5353.
Full textAbstract:
BackgroundAmong the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by gene mutations, such as the JAK2, MPL, and CALR genes, which regulate the JAK-STAT signaling pathway. ObjectiveThis study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. MethodsThe JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. ResultsThe JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. Six mutation types in CALR were identified in these neoplasms, one of which has not been previously reported. Additionally, one patient presented a double mutation in the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. ConclusionThus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.
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Benedetti, Edoardo, Rita Tavarozzi, Riccardo Morganti, et al. "Organ Stiffness in the Work-Up of Myelofibrosis and Philadelphia-Negative Chronic Myeloproliferative Neoplasms." Journal of Clinical Medicine 9, no. 7 (2020): 2149. http://dx.doi.org/10.3390/jcm9072149.
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To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9); however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p < 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.